title: Simvastatin for cognitive deficits and behavioural problems in patients with neurofibromatosis type 1 (NF1-SIMCODA): a randomised, placebo-controlled trial.
abstract: BACKGROUND
  Neurofibromatosis type 1 is a common genetic disorder characterised by neurocutaneous manifestations and cognitive and behavioural problems. Statins were shown to reduce analogous learning deficits in a mouse model of the disease, but a short-term trial in humans was inconclusive. We aimed to assess the use of simvastatin for the improvement of cognitive and behavioural deficits in children with neurofibromatosis type 1 for 12 months.
  
  
  METHODS
  In this randomised, double-masked, placebo-controlled trial, we recruited children with genetically confirmed neurofibromatosis type 1 aged 8-16 years from two national referral centres in the Netherlands and Belgium. Those with symptomatic CNS abnormalities or on neurotropic medication, including stimulants, were excluded. Eligible patients were randomly assigned (1:1) via a computer-generated, permuted-block list to simvastatin (10 mg per day in month 1, 20 mg per day in month 2, and 20-40 mg per day in months 3-12) or placebo for 12 months. Investigators, participants, and parents were masked to treatment assignment. Primary outcome measures were full-scale intelligence (Wechsler intelligence scale for children), attention problems (child behaviour checklist, parent-rated [CBCL]), and internalising behavioural problems (CBCL). We did intention-to-treat analyses (of all patients who had outcome data) using linear regression of the 12 month outcome scores, adjusted for baseline performance. This trial is registered with the Netherlands Trial Register, number NTR2150.
  
  
  RESULTS
  We randomly assigned 84 children to a treatment group (43 to simvastatin, 41 to placebo) between March 9, 2010, and March 6, 2012. We did not assess outcomes in two patients in the placebo group because they needed additional drug therapy. Simvastatin for 12 months had no effect on full-scale intelligence (treatment effect compared with placebo -1·3 IQ points [95% CI -3·8 to 1·3]; p=0·33), attention problems (-1·6 T-score points [-4·3 to 1·0]; p=0·23), and internalising behavioural problems (-0·1 T-score points [-3·3 to 3·1]; p=0·96). 38 (88%) of 43 patients on simvastatin and 39 (95%) of 41 patients on placebo reported adverse events, which were serious in two and four patients, respectively.
  
  
  CONCLUSIONS
  12 month simvastatin treatment did not ameliorate cognitive deficits or behavioural problems in children with neurofibromatosis type 1. The use of 20-40 mg simvastatin per day for cognitive enhancement in children with neurofibromatosis type 1 is not recommended.
  
  
  BACKGROUND
  The Netherlands Organization for Health Research and Development (ZonMw), Research Foundation Flanders (FWO-Vlaanderen), Marguerite-Marie Delacroix Foundation, and the Dutch Neurofibromatosis Association (NFVN).
authors.affiliation: Department of Neuroscience, Erasmus University Medical Centre, Rotterdam, Netherlands; Department of Paediatrics, Erasmus University Medical Centre, Rotterdam, Netherlands; ENCORE Expertise Centre For Neurodevelopmental Disorders, Erasmus University Medical Centre, Rotterdam, Netherlands.
authors.forename: Thijs
authors.initials: T
authors.lastname: van der Vaart
authors.forename: Ellen
authors.initials: E
authors.lastname: Plasschaert
authors.forename: André B
authors.initials: AB
authors.lastname: Rietman
authors.forename: Marleen
authors.initials: M
authors.lastname: Renard
authors.forename: Rianne
authors.initials: R
authors.lastname: Oostenbrink
authors.forename: Annick
authors.initials: A
authors.lastname: Vogels
authors.forename: Marie-Claire Y
authors.initials: MC
authors.lastname: de Wit
authors.forename: Mie-Jef
authors.initials: MJ
authors.lastname: Descheemaeker
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Vergouwe
authors.forename: Coriene E
authors.initials: CE
authors.lastname: Catsman-Berrevoets
authors.forename: Eric
authors.initials: E
authors.lastname: Legius
authors.forename: Ype
authors.initials: Y
authors.lastname: Elgersma
authors.forename: Henriëtte A
authors.initials: HA
authors.lastname: Moll
mesh_terms: D000293:Adolescent; D002648:Child; D002653:Child Behavior Disorders / Q000188:drug therapy* / Q000209:etiology; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009456:Neurofibromatosis 1 / Q000150:complications / Q000188:drug therapy*; D010919:Placebos; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010919:Placebos; D019821:Simvastatin